Discovery of the Migraine Prevention Therapeutic Aimovig (Erenumab), the First FDA-Approved Antibody against a G-Protein-Coupled Receptor

Abstract

In 2018, the United States Food and Drug Administration (FDA) approved Aimovig (erenumab) for the prevention of migraine. Erenumab is the first FDA approved antibody therapeutic against a G-protein-coupled receptor, the canonical receptor of calcitonin gene related peptide (CGRP-R). A novel, epitope-focused antigen was created to reconstruct the extracellular domains of the CGRP-R in a stable conformation. Successful inoculation of XenoMouse animals and careful screening yielded multiple candidate molecules for high potency and exquisite selectivity toward the CGRP-R over related receptors. These efforts led to the discovery of erenumab which has demonstrated the desired efficacy and safety profiles in multiple clinical studies for the prevention of migraine. The innovation developed in the discovery of erenumab furthers the ability to target G-coupled protein receptors using antibody approaches.

Conflict of interest statement

The authors declare the following competing financial interest(s): All authors are or were employed by Amgen Inc.

Copyright © 2019 American Chemical Society.

Figures

Figure 1

CGRP and related receptors of the calcitonin family. The CGRP receptor is similar in composition to several other members of the calcitonin family of receptors (receptor name listed above diagrams). These receptors are formed by a complex of the calcitonin-like receptor (CLR) or calcitonin receptor (CTR) with receptor-activity-modifying proteins (RAMPs 1–3), predominantly binding ligands CGRP, adrenomedullin (AM), and amylin (AMY). Due to the close similarity between receptor complexes, these agonists cross-react with other receptors of the family.

Figure 2

Design, purification, and competition binding assay of the soluble CGRPR-ECD Fc fusion protein immunogen. (A) Space-filling model of the theoretical structure of the CGRP-R ECD-Fc immunogen. This protein was constructed through fusing the N-terminal extracellular domains of RAMP1 and CLR (yellow and purple) to human IgG1 Fc domain (green). A 5× glycine linker was inserted between the extracellular domains and Fc region to confer additional flexibility and rotational freedom (orange). Coexpression of the two receptor components will generate a heterodimeric protein of 81.5 kDa. (B) MALDI-TOF mass data for native sample of CGRPR ECD-Fc immunogen. Peak 1 (76.1 kDa) represents the homodimer of RAMP1 ECD-Fc, peak 2 (86.3 kDa) represents the heterodimer of CGRP-R ECD-Fc (CLR + RAMP1), and peak 3 (99.1 kDa) represents CLR ECD-Fc. (C) Results of a fluorescence activated cell sorting (FACS)-based inhibition of ligand binding study, plotted as percent inhibition. Measured as percent reduction in binding of ALEXA-647 CGRP after 1 h of preincubation at room temperature with increasing concentrations of purified CGRP-R (ECD)-Fc. An Fc-fusion protein OPG-Fc was used as a negative control.

Figure 3

Functional selectivity screening of most potent CGRP-R antagonists. Large panel of 167 of the most potent CGRP-R antagonist hybridomas (>70% inhibition) were tested for functional activity in AMY1 (CTR+RAMP1) and AM1 (CLR+RAMP2) cell-based assays. The majority of samples tested showed little to no activity. A subset of the most selective hybridomas were then recombinantly expressed for potency determination.